Asthma Therapeutics: Recent Strides, New Hurdles

The prevalence of asthma continues to rise, with approximately 22.5 million sufferers now in the US alone. The inhalation
of corticosteroids remains a mainstay of treatment, reflecting the tenet that inflammation is an underlying feature of the
disease. The identification of alternative agents that might more specifically target inflammatory components and better control
the disease has proven problematic. Consequently, three recent positive announcements, from distinct phase 2 clinical trials,
have caused considerable excitement (1–3). For scientific investigators, biotechnology companies, patients, and clinicians, the possibility that decades of research
may finally translate into new treatments is welcome news indeed. But the importance of the disease will undoubtedly require
us to learn from and expand upon any success we encounter.

Classically, asthma has been regarded as an allergic (atopic) disease characterized by production of IgE and recruitment of
eosinophils, the latter orchestrated through an overly enthusiastic T helper 2 (Th2) cell immune response (Figure 1). This response entails the production of a panoply of cytokines, including interleukin-(IL)-4, IL-5, IL-13, as well as CC
chemokines, all on the background of a modified airway epithelium. These factors contribute to the hallmarks of the disease,
including a variable degree of bronchoconstriction, airway hyperresponsiveness (which is an increased sensitivity to a range
of noxious stimuli), and airway inflammation (4).

The traditional view of asthma, shown here in a simplified version, has become vastly more detailed over the past decade,
and a great many pathways of cell differentiation and signal transduction that modulate asthma have been identified, particularly
with the use of mouse models. But as nineteenth-century physiologist Claude Bernard observed, it is sometimes “what we think
we know that keeps us from learning.” New successes in asthma therapeutics (left), built upon “what we know,” appear to address
only certain patient types. The ongoing need for new asthma therapeutics may require researchers to broaden the types of questions
and metrics used in clinical development. (See text for details.)

Asthma can be punctuated by episodes of symptom exacerbation that are not adequately treated by the patient’s routine medication
and require emergency treatment. These episodes are associated with substantial morbidity and mortality and can incur significant
health care costs. In 2004, for example, exacerbations accounted for more than 80% of total direct costs for asthma with 1.8
million emergency room visits, 497,000 hospitalizations, and 4,055 deaths in the US alone (5).

Ideally, therapeutic strategies to treat asthma should address the twofold nature of the disease. They should not only provide
the relief that is typically afforded by corticosteroids, for example, to improve lung function, but should also address the
risks posed by symptom exacerbations. Indeed, the very attempt to define optimal control for any individual patient can be
a challenge as absolute diagnostic tests and biomarkers have remained unavailable. The lack of adequate biomarkers and diagnostic
tests, moreover, has been problematic for the clinical development of new drugs.

Given the variability of the disease and the complexities of individual patient responses, clinical studies in asthma require
rather large numbers of subjects—generally around 80–100 patients per variable studied. In early clinical studies, companies
have attempted to circumvent the need for large patient populations by establishing “proof-of-principle” endpoints, where
groups of 10–14 individuals might be challenged with a defined allergen. The results of such experiments have been commonly
extrapolated to predict whether drugs would likely alleviate the symptoms of asthmatics in their real-life environments (6). In the allergen challenge clinical research scenario, patients with a known sensitivity are exposed to a particular allergen
administered directly to the airways by means of an aerosol. The model typically seeks to evoke an asthmatic response that
would persist for several hours, characterized by a phase of initial bronchoconstriction prior to partial recovery and followed
by a longer-lasting “late phase” of bronchoconstriction. This late phase is associated with the influx of inflammatory cells,
particularly eosinophils, into the airways. Thus, the model provides for measures of airflow obstruction, inflammatory cells
and mediators in sputum, and airway responsiveness over time (6).

Based on this clinical model of allergen challenge, the inhaled antisense oligonucleotide ASM8 (Topigen/Pharmaxis) was reported
to reduce late-phase bronchoconstriction by 50% (p=0.002). ASM8 is comprised of two oligonucleotides: one targets expression of the chemokine receptor CCR3, found on a number
of inflammatory cells, including the eosinophil; the second targets expression of the β-chain common to the receptors for
a group of cytokines (e.g., IL-3, IL-5, and GM-CSF) produced by Th2 cells. Clinical responsiveness to ASM8 was dose-dependent,
with a daily dose of 8 mg over four days significantly affecting airway narrowing, chemically mediated hyperresponsiveness,
and eosinophil levels in sputum.

CYT003-QbG10 (hereafter abbreviated to QbG10; Cytos Biotechnology) has been similarly studied in sixty-three patients with
allergic asthma taking inhaled corticosteroids followed for twelve weeks. QbG10 is a virus-like (bacteriophage Qb–derived)
particle that carries a stretch of CpG oligonucleotides. The construct is designed to mimic bacteria in activating the innate
immune system. The original underlying premise was based on a balanced interplay between T-helper type 1 (Th1) and T-helper
type 2 (Th2) cells and their respective cytokine networks. Th2 cells and their cytokine repertoire have been implicated in
asthma; the design of CpG oligonucleotide-carrying QbG10 was envisaged to stimulate Th1 cells so that they would release cytokines
that suppress the “allergic” Th2 response. Recent studies suggest this concept might be an oversimplification and that Th1
cytokines are not required for efficacy (7). Seven subcutaneous injections of QbG10 significantly improved airway obstruction and asthma symptom scores, and also reduced
patient dependency on additional reliever medication (p=0.01). This study extends previous reports of beneficial effects of QbG10 in patients with allergic rhinitis and rhinoconjunctivitis,
and supports the notion that these disorders all share a common pathology.

In a third study, pitrakinra (Aerovance), which had previously shown a blunting of late-phase bronchoconstriction and other
effects in the clinical allergen challenge model (8), was administered as an inhaled dry powder at doses of 1, 3, or 10 mg, twice daily for twelve weeks to 534 patients with
moderate to severe asthma. This is a hard-to-treat population of patients who remain unstable despite routine inhaled corticosteroids
and bronchodilators in the form of long-acting β-agonists. At the highest dosage (10 mg), certain patients (having a particularly
large number of eosinophils in their airways) showed a significant reduction in asthma exacerbations (37%; p=0.004) and asthma symptoms. The drug is a 15kD recombinant protein that blocks the α-subunit common to both IL-4 and IL-13
receptors; IL-4 and IL-13 are thought to play a key Th2-cell–mediated role in asthma.

The Aerovance study is of interest for a number of reasons. First, the results are consistent with observed single nucleotide
polymorphisms in the relevant IL-4 receptor subunit (i.e., IL-4Rα), which are associated with severe asthma exacerbations,
reduced lung function, and increased airway inflammation (9). Second, the use of an IL-4 soluble receptor to suppress the activities of IL-4 did not show efficacy in asthma (10), suggesting that blocking the effects of both IL-4 and IL-13 might be necessary. However, AIR645 (Altair Therapeutics), an
antisense oligonucleotide that targets IL-4Rα expression, did not show any clinical benefit in the allergen challenge setting,
despite reducing IL-4R expression (11). Moreover, a monoclonal antibody against IL-4Rα, called AMG317 (Amgen), failed to elicit positive responses, in terms of
asthma exacerbations or asthma control, from patients with moderate to severe asthma (using an accepted asthma control questionnaire
as the primary endpoint) (12). The identification by Aerovance that only a particular subgroup of refractory eosinophilic asthmatics (i.e., less than 5%
of severe asthmatics) derives benefit from blocking IL-4Rα helps to explain the apparent anomalies. It also suggests that
exacerbations, at least in this patient subgroup, have a different underlying etiology from the day-to-day symptoms of asthma.
The apparent disconnect between bronchoconstriction and other important symptoms (i.e., exacerbations) is also highly informative.
For a long time, new treatments had focused exclusively on improving measures of bronchoconstriction, so that novel therapeutics
targeting other significant aspects of asthma might well have been overlooked.

The three recent clinical studies described above focused on allergic asthma. One emphasis of these studies [ASM8 (Topigen/
Pharmaxis) and pitrakinra (Aerovance)] was on cytokines and cytokine-mediated inflammatory cell responses that impact asthma-related
symptoms; upstream processes to these responses were also targeted [QbG10 (Cytos)]. The consistency of benefits that emerged
in the three separate studies, concomitant with interceding in the atopic cytokine–eosinophil nexus, is encouraging. However,
it is generally considered (amid significant debate) that only about 40–50% of asthmatics are atopic (13). Clearly, it is too early to predict patient populations that will benefit from ASM8, but the target groups for QbG10 and
pitrakinra are clearer, and the results show that treatment will not benefit the asthma population as a whole. Therein lies
the rub, but also the reality, of asthma therapeutics. It has been recognized for some time that “asthma” is a rubric for
a heterogeneous disorder, with any of a number of symptoms related to breathing difficulties. In 2006, an editorial in Lancet stated, “Asthma is at best a syndrome with different risk factors, different prognoses, and different responses to treatment”
(14). Consequently, any particular drug will likely not work in every patient, a simple statement with very important implications
for drug development. Specifically, companies that adhere uniformly to a simplified hypothesis of disease etiology may repeatedly
produce drugs that will be relevant to a single patient subgroup without offering anything new to the bulk of the patients.

Three critical components have contributed to the current state of affairs, in which the development of asthma therapeutics
may not be predicated on the realities and needs of the patient population. First, an extensive body of preclinical studies,
primarily in mouse models, has focused attention on the importance of Th2 cells and their cytokine repertoire as orchestrators
of the inflammatory response in asthma, stressing symptoms such as airway hyperresponsiveness (15). Although this focus has yielded compelling results, it is important to recognize that mice do not develop asthma spontaneously.
Rather, such an approach relies on a model of allergy, based on repeated injections of an allergen, often mixed with an adjuvant such as alum, which sensitizes the animals in
a highly artificial manner. More important, many of the features of asthma are not induced (16). Nevertheless, these models have continued to drive drug discovery efforts, and overall, the clinical results have been disappointing.

The oversimplification of complex syndromes by embracing convenient research practices is not the only source of difficulty.
The panoply of factors that culminate in asthma is in itself confounding, including environmental, genetic, and cellular variables.
To date, asthma has been characterized very poorly, often based on the level of bronchoconstriction rather than any underlying
biology. Researchers are thus placed in a very complicated situation. The pathologic features (e.g., involvement of cellular
inflammation) are similar in both allergic and non-allergic asthma, for example (17). Consequently, researchers have focused on reproducing the cellular response in airways in order to develop reductive theories.
By definition, preclinical models and target definition inevitably lag behind clinical recognition of critical aspects of
disease.

Finally, the problem is compounded by the difficulties of clinical development. As mentioned previously, most companies employ
an allergen challenge protocol in mild asthmatics with a known sensitivity to a particular allergen (6). This proof-of-principle study design thus promotes the standardization of response measurement and uniformity in experimental
design so as to limit the need to examine large patient populations. Thus, unique compounds that might target aspects more
prominent in certain asthma subgroups, particularly those asthma sufferers who are not atopic, will be missed. Aerovance could
be considered extremely lucky to have shown activity in the allergen challenge setting (7) sufficient to justify moving into further clinical trials; the company’s ultimate evidence of reduced exacerbations in refractory
eosinophilic asthmatics is far removed from the profile suggested by the initial allergen challenge results. The result is
analogous to the story of Mepolizumab (GSK), a monoclonal antibody to IL-5 that had no clinical effect on bronchoconstriction
or airway hyperreactivity in the allergen challenge setting (although it did decrease blood and sputum eosinophils) (18). Nevertheless, this drug was eventually found to reduce asthma exacerbations in severe eosinophilic asthmatics (19, 20), with only marginal improvements in standardized measurements (21). This success story was highly dependent on the rich resources that supported GSK’s pursuit past initial results that might
well have discouraged many biotechnology companies. The story’s success in fact prompted the conclusion that “eosinophils
are not the only (or perhaps even the major) cell involved in disease pathogenesis, even in patients with severe asthma” (21). This valid interpretation emasculated decades of research. This perspective should serve as a reminder to temper enthusiasm
(e.g. over ASM8) until activity is shown in clinical asthma settings beyond allergen challenge.

Recent successes in rational drug discovery efforts in asthma, built on decades of basic research, are promising and are especially
encouraging in consideration of the hindrances inherent in developing asthma drugs. But it is the perseverance and dedication
of companies such as Topigen/Pharmaxis, Cytos Biotechnology, and Aerovance, coupled with the insights of top-flight consultants
sensitive to how the field is unfolding, that have enabled new paths to therapeutic discovery in asthma. These successes reflect
important intellectual liberalism and flexibility of clinical trial design (incorporating predefined subgroups representing
specific phenotypes, and new end-points, for example), coupled with a willingness to explore new avenues. Asthma is the quintessential
example of the demand for personalized medicine. Better identification of patient groups and their underlying cellular biology
will be key to determining who will benefit from experimental treatments. It is certainly possible that asthma medications
previously discarded, owing to weak clinical trial data in a limited setting, might be resurrected.

Focusing on the etiology and biology of asthma exacerbations, first steps are made towards trying to identify an exacerbation-prone
phenotype as a particular subset of asthmatics that are difficult to manage as they have a range of underlying factors and
co-morbidities.

(1999) How much asthma is really attributable to atopy. Thorax54:268–272.

Although recognizing that the terms “asthma” and “atopy” are both poorly defined, the authors evaluate multiple published
studies to determine how much asthma can be attributed to atopy, using different measures (positive skin prick tests, serum
IgE levels), concluding it is less than 50%.

In an editorial accompanying two pivotal studies with mepoluzimab [see references (19) and (20)], the results are put in perspective regarding the population that would benefit from the drug and what it means to the
prevailing scientific concepts of asthma.

Kevin Mullane, PhD, has spent over twenty-five years managing R&D efforts in academia and multinational pharmaceutical and small biotechnology
companies. He was recently President and CEO of an inflammation/immunology company with a focus on respiratory ailments such
as asthma. E-mail
kevinmullane{at}comcast.net.